The discovery of the Huntington's disease gene in February of 1993 generated optimism that the genetic mechanisms underlying the cause of this disease would yield to studies directed at the patterns of gene expression, protein localization and the elucidation of the interactions of the huntingtin protein with other proteins. In the intervening 9 years, progress has been made in all of these areas and yet the disease remains largely undeciphered. Two significant discoveries are pertinent to this application. First, transgenic "Huntingtin" mice, containing an expanded trinucleotide repeat, provide opportunities to investigate possible pharmacologic interventions in HD, and yet the selection of agents to be tested in this important animal model remains largely one of trial and error. Second, the discovery of 24 "hunting associated proteins" or HAPs, which bind to huntingtin, provide a series of potential candidate genes that may interact with or modify the disease expression. However, the number of proteins that interact with huntingtin is sufficiently numerous that it is difficult to investigate all of them extensively. We are faced with the research challenge to explore the significance of each HAP, and to deliver information about possible mechanisms that may be invoked for therapeutic interventions in HD. The Project 2 of the New England HD enter is directed at these two goals. We propose to develop three patient samples that will permit an evaluation of the clinical significance of each HAP and will further permit the exploration of the presence of other genetic modifiers of the huntingtin gene and of disease expression. These samples include (1) an international collaboration to collect 1000 HD affected sibling pairs, (2) a clinical sample of 200 HD diagnosed patients followed longitudinally through our HD Center affiliated clinics, and (3) a series of more than 300 highly characterized HD postmortem brain specimens. With these resources, we are able to document age at onset (in all three samples), rte of disease progression (clinic sample), pathological involvement (brains sample). Utilizing linkage methods in the sibling pairs, and association methods in the other two samples, we propose to investigate the presence of a genetic modifier linked to the HD allele on the normal chromosome, the clinical significance of the HAPs and to explore other possible genetic modifiers of HD. The identification of modifiers of HD holds promise for the recognition of substances which may be involved for pharmacologic intervention in the disease.